GI Cancer Expert Sets Sights on the Next Generation

When Weijing Sun, MD, FACP, started his career in oncology more than 30 years ago, the choice of medical treatment for patients with gastrointestinal (GI) malignancies was dominated by fluorouracil (5-FU), regardless of the tumor type.

“For treating all GI cancer, the only really effective drug was 5-FU,” Sun recalled in a recent interview with OncologyLive^®. “If you were treating colon cancer, it was 5-FU; stomach cancer, it was 5-FU. We tried to modify the regimen by prolonging infusion, with weekly infusion or daily infusion. We tried to maximize the benefit.”

Instead of becoming discouraged by such limited options, Sun was motivated to explore potential new treatments with drug development. He became a prolific investigator into novel agents and combinations across a range of GI malignancies, serving as an institutional principal investigator in more than 40 clinical trials involving hepatocellular carcinoma (HCC) and colorectal, esophageal, gastric, and pancreatic cancers.

Today, Sun is an internationally known GI cancer expert. He is the Sprint Professor of Medical Oncology and director of the Medical Oncology Division at The University of Kansas School of Medicine and associate director of The University of Kansas Cancer Center (KU Cancer Center), a National Cancer Institute (NCI)–designated comprehensive cancer center, both headquartered in Kansas City.

Although he retains an interest in research, some of Sun’s focus has shifted to serving as a physician leader seeking to foster discussion about optimal treatment strategies among practicing oncologists and mentoring the next generation of providers. In that capacity, Sun is helping to shape the agenda for the upcoming 19th Annual Meeting of the International Society of Gastrointestinal Oncology^® (ISGIO^®), which is scheduled to take place September 30 through October 1, 2022, in Nashville, Tennessee. Sun serves as president of ISGIO^® and is cochairing the meeting (Sidebar).

“Our job is not just for ourselves but for the younger generation—to be their mentor, to encourage them, train them, and guide them,” said Sun, noting that many GI physicians have been practicing 30 years or longer. “We’re obligated to transfer the baton to the next generation.”

“Physician leaders are important,” he noted. “You do have some authority, you do have a voice in pushing or guiding research funding, finding resources, or using your expertise and knowledge to guide and help afford training for the younger generation. That’s one of the reasons why I am involved and interested in doing some administrative jobs.

“Of course, I’m still seeing patients in clinical trials,” he added. “Sometimes it seems like I have 3 jobs. Sometimes it’s overwhelming, sometimes it’s tiring. On the other hand, the reward is something you might not be able to see. . . You have a voice. If you’re not at the table, you don’t know what was discussed.”

Among his colleagues, Sun is known for his collaborative spirit. “He has been a lifelong contributor to GI cancer research and team science and has made a significant impact on that,” said John Marshall, MD, chief of the division of hematology/oncology at Medstar Georgetown University Hospital and director of the Otto J Ruesch Center for the Cure of Gastrointestinal Cancer, both in Washington, DC. “He is one of those people who represent what is good about the field. He gets the big picture and is engaged in making sure the next generation comes along but also is the kind of person who will share thoughts that are sometimes are hard to share.”

In addition to his research activities, Sun has helped shaped the conversation in GI malignancies through his participation in cooperative group steering committees and task forces, conference program committees, and editorial boards of peer-reviewed journals, noted Tanios S. Bekaii-Saab, MD, a professor at Mayo Clinic College of Medicine and Science and a consultant in the Division of Hematology/ Oncology at Mayo Clinic in Scottsdale, Arizona. Bekaii-Saab serves as program chair for the upcoming ISGIO meeting.

“He is definitely one of the most prominent figures in gastrointestinal cancers not just nationally, but internationally,” Bekaii-Saab said. “He has really developed his career and expertise with a focus on drug development with biologic and targeted therapies and, more so these days, focused on immune-related research. . . He’s one of the prominent figures in GI oncology who have helped transform the field in many ways.”

Advancements in GI Landscape

Although Sun sees many unmet needs throughout the GI cancer field, particularly in pancreatic cancer, he said encouraging findings were presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting in 3 major areas: (1) results of a large-scale study that help guide the treatment of patients with metastatic colorectal cancer (mCRC); (2) evidence of complete responses (CRs) with single-agent immune checkpoint inhibitor therapy for a subset of patients with locally advanced rectal cancer; and (3) signs of clinical utility for circulating tumor DNA (ctDNA) analysis to help inform adjuvant therapy recommendations for colon cancer.^1-3

A New Standard Forms in mCRC

In the phase 3 PARADIGM trial (NCT02394795), investigators sought to determine whether the addition of an EGFR inhibitor vs a VEGF inhibitor to chemotherapy would be a more effective regimen for patients with unresectable RAS wildtype mCRC. Previous studies in drugs with these mechanisms have yielded inconsistent results.¹

In PARADIGM, patients were randomly assigned to receive either panitumumab (Vectibix), an EGFR inhibitor, or bevacizumab (Avastin), a VEGF inhibitor, plus modified FOLFOX-6 (oxaliplatin, leucovorin calcium, and 5-FU). The FDA has approved both agents for mCRC settings,^4,5 but PARADIGM is the first trial to compare the drugs plus standard chemotherapy prospectively.¹

Although patients with unresectable disease on either side of the colon were eligible to participate in the study, the primary end point was overall survival (OS) in participants with a left-sided primary tumor, defined as the descending colon, sigmoid colon, rectosigmoid, and rectum. If that benchmark proved statistically significant, defined as P < .04202, the OS in the overall population would be calculated, with a P < .05 threshold for significance.

Overall, 823 patients were recruited from May 2015 to June 2017. The efficacy-evaluable population comprised 400 patients in the panitumumab arm, including 312 with left-sided disease, and 402 patients in the bevacizumab arm, including 292 with left-sided tumors.

After a median follow-up of 61 months, the median OS among patients with left-sided tumors favored panitumumab at 37.9 months (95.8% CI, 34.1-42.6) compared with 34.3 months (95.8% CI, 30.9-40.3) with bevacizumab (HR, 0.82; 95.8% CI, 0.68-0.99; P = .031). In the overall population, median OS was 36.2 months (95% CI, 32.0-39.0) with panitumumab vs 31.3 (95% CI, 29.3-34.1) with bevacizumab (HR, 0.84; 95% CI, 0.72-0.98; P = .030). However, a subgroup analysis showed that panitumumab was not more beneficial than bevacizumab for patients with right-sided tumors (HR, 1.06; 95% CI, 0.77-1.45).¹

The findings support panitumumab plus modified FOLFOX-6 as a first-line therapy for patients with RAS wild-type left-sided mCRC, investigators concluded. “That’s very important because it confirms the treatment standard for this population,” Sun said.

Immunotherapy Stirs Excitement in Rectal Cancer

In the rectal cancer field, initial results from a phase 2 study (NCT04165772) suggest that single-agent therapy with dostarlimab-gxly (Jemperli), a PD-1 inhibitor, may enable patients with mismatch repair–deficient (dMMR) locally advanced disease to avoid the debilitating effects of other therapeutic options.²

Single-agent therapy with dostarlimab, administered intravenously at 500 mg every 3 weeks for 6 months, resulted in a 100% CR rate in the first 14 patients, according to findings presented at 2022 ASCO and reported simultaneously in the New England Journal of Medicine.⁶ After a median follow-up of 6.8 months, none of the patients needed the standard treatment options of chemotherapy, radiation, or surgery.

“This is very, very encouraging and almost a surprise,” Sun said, adding that there was no evidence of tumor on endoscopic and MRI follow-up evaluations. “We probably need some larger study to verify the information, but this could change the way we’re treating this small relatively specific patient population.”

The first goal of treatment for patients with rectal cancer is curative therapy, Sun noted, but it also is important to preserve rectal function, if possible.

The findings have implications not only for patients with dMMR rectal cancer, estimated at 5% to 10% of those diagnosed with the malignancy, but in other tumor types, according to investigators. The population of patients with tumor-agnostic, dMMR early-stage disease represents about 3% to 4% of all cancers, they said.² In February 2022, the FDA granted an accelerated approval to dostarlimab for patients with dMMR recurrent or advanced solid tumors after prior therapy.⁷

ctDNA Technology Moves Forward

The traditional TNM system for staging cancers by evaluating the primary tumor, regional lymph nodes, and distant metastasis has many limitations when used to assess whether patients with colon cancer would benefit from adjuvant therapy, Sun said. Some patients are treated unnecessarily, he explained, resulting in more toxicity from chemotherapy than benefit from treatment.

Against this backdrop, Sun said, developments in ctDNA technology offer the potential for noninvasive monitoring that helps guide treatment decisions, particularly for patients at high risk of recurrence. Study data have suggested that high levels of ctDNA in the blood correlate with a poor prognosis, Sun noted.

At ASCO 2022, findings from the DYNAMIC trial (ACTRN12615000381583) demonstrated that ctDNA levels correlated with recurrence-free survival (RFS) in patients with fully resected stage II colon cancer, with no evidence of metastatic disease on a CT scan within 8 weeks of surgery. Investigators randomly assigned participants 2:1 to ctDNA-guided treatment vs standard adjuvant therapy based on conventional clinicopathologic criteria. The primary end point was the RFS rate at 2 years.³

For the ctDNA arm, investigators conducted targeted sequencing on resected tumor tissue to identify mutations unique to each patient’s tumor from a panel of 15 genes recurrently altered in CRC. If at least 1 of these mutations was detected, ctDNA derived from plasma was analyzed at weeks 4 and 7 for the presence of the aberration. Participants with a positive ctDNA result at either testing point received adjuvant chemotherapy therapy with an oxaliplatin-based doublet or single-agent fluoropyrimidine, whereas those with a negative result went on to observation.

The intent-to-treat population was comprised of 294 patients in the ctDNA-guided arm and 147 participants in the standard-therapy group. In the ctDNA group, 45 patients (15%) went on to receive adjuvant chemotherapy; all patients in the standard-management arm had chemotherapy.

After a median follow-up of 37 months, the 2-year RFS rate was 93.5% with ctDNA-guided therapy vs 92.4% with standard protocols. The 1.1% difference in the rate (95% CI, —4.1% to 6.2%) confirmed the noninferiority of the ctDNA-guided strategy, investigators said. The 3-year RFS rate was 92.5% for patients with negative ctDNA compared with 86.4% for those with positive levels. Investigators said the low recurrence rate among patients with negative ctDNA shows that they are unlikely to benefit from chemotherapy.³

Although the DYNAMIC trial attracted attention at 2022 ASCO, many other studies into the clinical utility of ctDNA in GI cancers are ongoing, Sun noted.

Impact of Early-Phase Research

Over the years, Sun has published more than 125 peer-reviewed articles and presented approximately 100 abstracts and posters at conferences. At 2022 ASCO, he and colleagues presented early f indings from a phase 2 study (NCT03488667) into the use of perioperative therapy with pembrolizumab (Keytruda) plus FOLFOX in patients with newly diagnosed locally advanced adenocarcinoma of the distal esophagus, gastroesophageal junction, and stomach.⁸

Participants in the study receive neoadjuvant therapy with pembrolizumab at 200 mg every 3 weeks for 3 doses plus mFOLFOX every 2 weeks for 4 doses and then proceed to surgical resection if there is no evidence of metastatic disease. Following surgery, participants receive adjuvant therapy with mFOLFOX every 2 weeks for 4 doses plus pembrolizumab at 200 mg every 3 weeks for 12 doses. The primary end point is pathological response rate (ypRR) with a tumor regression score (TRS) of 2 or less.

Of 37 patients who finished preoperative treatment at the time of the 2022 ASCO presentation, 29 participants went on to receive curative- intent (R0) resections. Of those who had surgery, 26 patients (90%) demonstrated a pathological response (ypRR) with TRS of 2 or less, including 6 patients (20%) who achieved a complete ypRR with a TRS of 0. Overall, 21 patients completed all phases of the treatment plan; 2 patients had recurrent or metastatic disease at 9 months and 10 months, respectively, and 1 patient died 23 months after enrollment. The other patients were cancer free at the time of the presentation.

The findings show that the combination can be safely administered, and the efficacy data are “very encouraging,” Sun and colleagues said.

Early-phase data such as those of the ASCO presentation might not produce immediate results but are helpful in setting the stage for future investigations, Sun said. When asked which research accomplishment he was most proud of, Sun pointed to studies he conducted in the mid-2000s into the combination of bevacizumab plus chemotherapy for treating patients with advanced or metastatic HCC. At the time, bevacizumab was approved for mCRC. Sun’s findings showed that the combination was a tolerable and effective option for this population.^9,10

Although that regimen has not been approved for liver cancer, bevacizumab entered the HCC paradigm in June 2020 in combination with atezolizumab (Tecentriq), a PD-L1 inhibitor, for patients with unresectable or metastatic HCC who have not received prior systemic therapy.¹¹

“These kinds of early data are very important,” Sun said. “Sometimes the reward may not necessarily be recognized immediately but the reason we do science is to try and advance the science to make the treatment option available. It’s not because want to be popular or to be famous.”

In that regard, Sun has extensively explored the role of angiogenesis, the process of blood vessel formulation that feeds tumor growth, in HCC and other GI malignancies. As a VEGF inhibitor, bevacizumab is perhaps the best-known anticancer therapy that targets angiogenesis.^12-14

A Far-Flung Career

In terms of his career, Sun’s journey had been as diverse as his research portfolio. After attaining his medical degree from Shanghai Medical University (now Fudan University) in in China in 1982, Sun practiced there for several years before immigrating to the United States in the late 1980s where he participated in postdoctoral and clinical fellowship programs. In 2001, Sun joined the faculty of the University of Pennsylvania School of Medicine in Philadelphia, Pennsylvania, as an assistant professor. He rose through the ranks to become director of GI medical oncology at the school of medicine and at the university’s Abramson Cancer Center from July 2008 through July 2012.

In September 2012, Sun joined the University of Pittsburgh School of Medicine, also in Pennsylvania, where he was director of the GI cancers section of hematology-oncology and codirector of the UPMC Gastrointestinal Cancer Prevention and Treatment Center.

Five years ago, Sun accepted his current multifaceted roles at the University of Kansas. In doing so, he went from a state with 5 NCI–designated centers, including 3 cancer centers and a basic laboratory cancer center in Philadelphia alone, to a state where there is one. KU Cancer Center became the state’s only NCI-designated cancer center in 2012.¹⁵

In July 2022, KU Cancer Center was recognized as a comprehensive cancer center, a designation encompassing a greater depth and breadth of research that has been awarded to 53 centers nationwide. The honor caps a nearly 20-year effort to gain the NCI’s highest status, and KU Cancer Center leaders expect the designation will open the door to an increase in federal research funding.¹⁶

Sun said the center’s pursuit of comprehensive cancer center status was one of the reasons he accepted a position there. Many medical resources are concentrated on the East and West coasts, while patients in rural or otherwise underserved populations have unmet needs, he observed. “If I can contribute to making the cancer center a high-level [institution]—the university is one of the tops in the nation now—that will be a tremendous reward for me personally,” he said.

References

1. Yoshino T, Watanabe J, Shitara K, et al. Panitumumab (PAN) plus mFOLFOX6 versus bevacizumab (BEV) plus mFOLFOX6 as first-line treatment in patients with RAS (WT) wild-type metastatic colorectal cancer: results from the phase 3 PARADIGM trial. J Clin Oncol 2022;40(suppl 16):LBA1. doi:10.1200/JCO.2020.40.16_suppl.LBA1
2. Cercek A, Lumish MA, Sinopoli JC, et al. Single agent PD-1 blockade as curative-intent treatment in mismatch repair deficient locally advanced rectal cancer. J Clin Oncol. 2022;40(suppl 17):LBA5. doi:10.1200/JCO.2022.40.17_suppl.LBA5
3. Tie J, Cohen JD, Lahouel K, et al. Adjuvant chemotherapy guided by circulating tumor DNA analysis in stage II colon cancer: the randomized DYNAMIC trial. J Clin Oncol. 2022;40(suppl 17):LBA100. doi:10.1200/JCO.2022.40.17_suppl.LBA100
4. Vectibix. Prescribing information. Amgen Inc; 2021. Accessed July 31, 2022. https://bit.ly/3QbP6EH
5. Avastin. Prescribing information. Genentech, Inc; 2020. Accessed July 31, 2022. https://bit.ly/3JhBo0Q
6. Cercek A, Lumish MA, Sinopoli JC, et al. PD-1 blockade in mismatch repair-deficient, locally advanced rectal cancer. N Engl J Med. 2022 ;386(25):2363-2376. doi:10.1056/NEJMoa2201445
7. FDA grants accelerated approval to dostarlimab-gxly for dMMR advanced solid tumors. FDA. Updated February 1, 2022. Accessed July 31, 2022. bit.ly/3whe2C6
8. Sun W, Saeed A, Al-Rajabi RMT, et al. A phase II study of perioperative mFOLFOX plus pembrolizumab combination in patients with potentially resectable adenocarcinoma of the esophageal, gastroesophageal junction (GEJ) and stomach. J Clin Oncol. 2022;40(suppl 16):4047. doi:10.1200/JCO.2022.40.16_suppl.4047
9. Hewitt MR, Sun W, Haller DG, et al. A phase II trial of combination of capecitabine, oxaliplatin with bevacizumab in treatment of advanced hepatocellular carcinoma (HCC): preliminary safety analysis. J Clin Oncol. 2006;24(suppl 18):14098. doi: 10.1200/jco.2006.24.18_ suppl.14098
10. Sun W, Haller G, Mykulowycz K, et al. Combination of capecitabine, oxaliplatin with bevacizumab in treatment of advanced hepatocellular carcinoma (HCC): a phase II study. J Clin Oncol. 2007;25(suppl 18):4574. doi:10.1200/jco.2007.25.18_suppl.4574
11. NCI staff. Atezolizumab plus bevacizumab approved to treat liver cancer. Cancer Currents blog. June 4, 2020. Accessed August 2, 2022. https://bit.ly/3Jo4Q5n
12. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-74. doi:10.1016/j.cell.2011.02.013
13. Morse MA, Sun W, Kim, R. The role of angiogenesis in hepatocellular carcinoma. Clin Cancer Res. 2019;25(3):912-920. doi:10.1158/1078-0432.CCR-18-1254
14. Saeed A, Park R, Sun W. The integration of immune checkpoint inhibitors with VEGF targeted agents in advanced gastric and gastroesophageal adenocarcinoma: a review on the rationale and results of early phase trials. J Hematol Oncol. 2021;14(1):13. doi:10.1186/ s13045-021-01034-0
15. Find a cancer center. National Cancer Institute. Accessed August 2, 2022. https://bit.ly/3vY1ErZ
16. Hawes K. The University of Kansas Cancer Center earns National Cancer Institute’s most prestigious status—Comprehensive. University of Kansas Medical Center. July 7, 2022. Accessed August 2, 2022. https://bit.ly/3zQOq2f